Osteoporosis is a major health problem affecting nearly 1.5 million people every year. The reduction of sex hormone levels in both men and women increase production of certain factors that lead to osteoporosis. One-third of all post-menopausal Caucasian women experience at least osteoporotic fracture during their lifetime. In addition, more than 70 percent of patients with advanced breast or prostate cancer have skeletal metastases leading to bone degradation due to osteoclastogenesis. Ongoing osteoclast activity appears to be involved in the generation and maintenance of ongoing and movement-evoked pain. Blockade of ongoing osteoclast activity appears to have the potential to reduce bone cancer pain in patients with advanced tumor-induced bone destruction. Recent studies have shown that RANKL, a member of the tumor necrosis factor superfamily, by acting through its receptor RANK can induce osteoclast formation leading to osteoporosis. In the present study, we propose to identify peptide inhibitors by screening peptide display libraries. The ability of these peptides to interfere with RANKL induced osteoclast formation will be tested. The inhibitory effect of selected peptides in animal models will be tested in the Phase II study. The selected peptides can be used to design even smaller peptides or small molecule non-peptide mimetics, which can be used as therapeutic drugs.